Lymphatic system imaging is important for diagnosis of lymph nodes in nuclear medicine. In cases of breast cancer and melanoma, excessive excision can be avoided during surgery if sentinel lymph node, the closest lymph node to the tumor tissue, can be detected by injecting radiocolloid into the tumor. The detected sentinel nodes are subject to biopsy to detect metastases of which presence would affect the decision making for excision. This is very important for after-surgery adverse reaction and cosmetic. (G. Mariani, L. Moresco, G. Viale, G. Villa, M. Bagnasco, G. Canavese, J. Buscombe, H. W. Strauss, G. Paganelli. “Radioguided sentinel lymph node biopsy in breast cancer surgery.” J. Nucl. Med. 2001; 42:1198-1215; G. Mariani, M. Gipponi, L. Moresco, G. Villa, M. Bartolomei, G. Mazzarol, M. C. Bagnara, A. Romanini, F. Cafiero, G. Paganelli, H. W. Strauss. “Radioguided sentinel lymph node biopsy in malignant cutaneous melanoma” J. Nucl. Med. 2002; 43:811-827)
Lymph nodes can be imaged using an adequate radiocolloid which is injected into tissue and is successively moved and trapped into lymph nodes. The lymph node in which radioactivity is accumulated can be detected by a gamma probe. Most of the radiopharmaceuticals used for imaging and detection of lymph nodes are 99mTc labeled colloids such as antimony sulfur colloid (10˜20 nm), albumin nano colloid (50 nm), and sulfur colloid (100˜200 nm). The colloids with smaller particle size are more ideal because of rapid lymph node uptake. Antimony sulfur colloid is the best agent among currently used colloids because of the smallest particle size. However, its particle size is still too big and it requires 2 hr boiling time for labeling which is not adequate for the patients who should go to surgery in the early morning. In addition, it can become unstable after neutralization, which is prepared in strong acid medium.
To solve the problems, 99mTc-human serum albumin (HSA) has been used, which has particle size of 6˜8 nm. 99mTc-HSA can be labeled rapidly and shows rapid movement to lymph nodes. However, it shows low contrast lymph node images and uptakes not only in sentinel lymph nodes but also in other lymph nodes because it does not accumulate in but bypasses the lymph nodes. (W. T. Phillips, T. Andrews, H.-L. Liu, R. Klipper, A. J. Landry Jr, R. Blumhardt, B. Goins. “Evaluation of [99mTc] liposomes as lymphoscintigraphic agents: comparison with [99mTc] sulfur colloid and [99mTc] human serum albumin” Nucl. Med. Biol. 2001; 28:435-444)
To solve the problem, a new radiopharmaceutical, so called disulfide reduced mannosylated human serum albumin (MSA), which can strongly binds with mannose receptors existing on immune cells, is easy to label with 99mTc, has adequate molecular size to be absorbed to lymph capillary, and has no adverse reaction to human body, was developed. (Korean Patent 10-0557008, Disulfide reduced mannosylated serum albumin for lymphoscintigraphy and radiolabeled compounds comprising it. Feb. 23, 2006; Jeong J M, Hong M K, Kim Y J, Lee J, Kang J H, Lee D S, Chung J K, Lee M C. Development of 99mTc-neomannosyl human serum albumin (99mTc-MSA) as a novel receptor binding agent for sentinel lymph node imaging. Nucl Med Commun. 2004 25(12):1211-7) It is known that MSA can strongly bind with mannose receptor (P. Stahl. Et al, Cell 1980; 19:207˜215). So in the above patent, it was postulated that the lymph nodes can be imaged if MSA is labeled with an adequate radionuclide for imaging such as 99mTc. Furthermore, MSA would show more rapid lymph node uptake because of its small size 6˜8 nm. However, MSA itself cannot be labeled with 99mTc without modification. So, disulfide reduced MSA was prepared by treating it with adequate reducing agents such as β-mercaptoethanol and dithiothreitol. There is a report that disulfide reduced galactosylated or lactosylated human serum albumin is labeled with 99mTc after reducing disulfide bonds by treating with reducing agents. (Korean Patent 0464917. New disulfide reduced galactosylated serum albumin thereof; a liver function imaging composition; and a radiolabeled compound comprising it. Dec. 24, 2004) However, these 99mTc-labeled agents cannot be imaged by positron emission tomography (PET).
Recently, the need for positron labeled radiopharmaceuticals for immune cell imaging increased, because PET is widely spread due to its superiority to conventional gamma images, and furthermore, positron or beta probes for detecting metastases are developed. Generally, positron emitters such as and 18F, 11C, 13N, and 15O are produced by cyclotron. Among these, only 18F is applicable for lymph node imaging because of its relatively long half-life (110 min) compare to other radionuclides. However, its labeling procedure requires evaporation and heating at high temperature, those are complicate and causes of protein denaturation. Moreover, production of 18F requires expensive cyclotron system.